Reviews

In 1996, intraperitoneal (IP) administration of cisplatin plus intravenous (IV) cyclophosphamide proved superior to both drugs given intravenously at the same doses—which, at the time, was the standard treatment in the United States. The IP ‘option’ was not adopted, however, because the standard treatment had shifted to IV cisplatin plus paclitaxel. Two additional phase III trials by the Gynecologic Oncology Group (GOG) comparing IP versus IV cisplatin, but including other variables, have shown similar superior effects of the IP route on outcome, but with toxicities—particularly local tolerance and neuropathy—increased. An ongoing trial by the GOG is again looking into an IP versus IV comparison, and introducing in one of the IP arms the substitution of IP carboplatin for IP cisplatin. All three arms of this trial contain bevacizumab (Avastin). Two other trials comparing IV versus IP administration of platinums or platinums and paclitaxel have just been launched, led by Japanese and Canadian investigators, respectively. While awaiting additional data on the ongoing debate over IP versus IV therapy, it is important that we consider issues concerning why the IP route may be relevant, how can one increase the safety of this route, and who should be treated and with what drugs, particularly when faced with a patient outside the clinical trials setting. The underlying hypothesis for use of IP therapy is based on the existence of a dose-effect relationship for platinum drugs in ovarian cancer. We review the known data on this relationship, and explore why interest in platinum drugs has become the central focus of ovarian cancer treatment.

Epithelial ovarian cancer (EOC) spreads prominently within the peritoneal cavity. In fact, we now know that high-grade serous cancers are often of tubal origin, and their presentation as tubo-ovarian masses renders it likely that intraperitoneal spread occurs as an early event in their clinical evolution. From the outset, IP drug administration in ovarian cancer conferred a pharmacologic advantage over IV administration, given the additional clinical benefit derived from achieving more efficient control of life-threatening peritoneal disease.[1]

The systemic treatment of epithelial ovarian cancer and related extrauterine adenocarcinomas of Mullerian origin relies on ‘platinum-based’ chemotherapy. Ever since the introduction of cisplatin into our armamentarium in the late 1970s,[2] this drug, and later its less toxic analog, carboplatin, have provided the platform for treatment of these malignancies at all stages. Adoption of cisplatin as standard treatment accelerated with the discovery of effective antiemetics, and introduction of the equally efficacious carboplatin, with its more predictable pharmacokinetics and superior safety profile, led to wide exploration of dose-response relationships.[3,4] Before meta-analyses were in vogue, William Hryniuk and colleagues observed that in ovarian cancer trials, the dose of cisplatin correlated with improved survival.[5] However, evidence for benefit beyond a certain ‘dose-intensity’ was not obvious.[6] As Martin Gore noted in a 2003 editorial in the Journal of Clinical Oncology, “Devotees of the ‘more is better’ school of oncology must face the uncomfortable truth that the majority of randomized trials have failed to show an overall survival benefit associated with an increase in the total dose or dose-intensity of platinum.” He went on to state, however, “Any discussion of dose-response in ovarian cancer is incomplete without a reference to the subject that always guarantees a thoroughly entertaining argument: namely, intraperitoneal chemotherapy. The data from randomized trials of intraperitoneal chemotherapy do support the premise that a dose-response exists....”[7]

TABLE 1Results of the Three GOG Phase III Trials and Key Criticisms Against Their Message

This discussion is still applicable from today’s perspective, but it has become even more relevant than when Gore’s editorial was written. In 2006 the US National Cancer Institute (NCI) issued a clinical announcement[8] after the results of the third of phase III GOG trials (GOG172) on IP versus IV became known and were subsequently published (by Armstrong, in the New England Journal of Medicine, in 1996, and others).[9-11] After reviewing the data from the IP versus IV phase III clinical trials conducted by the GOG (Table 1), the NCI announced, “Based on the results of these randomized phase III trials, a combination of IV and IP administration of chemotherapy conveys a significant survival benefit among women with optimally debulked epithelial ovarian cancer, compared to IV administration alone.” Further, the NCI urged physicians to become familiar with these trials and, if necessary, refer patients to centers familiar with IP drug delivery. Both in the US and Europe, reaction to such announcement was swift: Ozols and colleagues noted that “…exploratory cross-trial comparisons of IV carboplatin/paclitaxel compared to IP regimens suggest very similar efficacy in optimal stage III disease,”[12] and Gore et al argued, ‘There are at least eight reasons why the Armstrong article does not support the use of IP administration as a standard of care.”[13]

A major problem in the adoption of IP therapy as the new standard for optimally debulked ovarian cancer might be put forth in a format analogous to the title of Gore’s 2003 editorial in JCO: “IP Cisplatin Is More Effective than IV Cisplatin: But How Do I Prescribe It?”[7] Figure 1 shows the schema of GOG172 and Figure 2 graphically lays out many of the disputed areas in GOG172, including: Is IP paclitaxel necessary to achieve the results? Is the dose of IP cisplatin of 100 mg/m2 acceptable to many patients? How does one deal with the 24-hour infusions of paclitaxel? If one had used a carboplatin control, would the survival differences have been significant? Can one advocate a treatment with a 42% completion rate? And, is the tradeoff of adverse quality of life for a few months and risk of treatment complications from IP therapy for a less than 20% reduction in risk of dying reasonable? GOG investigators struggled with these issues, and after a series of pilot studies embarked in late 2009 on another IP versus IV phase III study (GOG252) containing also an IP toxicity–reduction arm, based on IP carboplatin and phase II data from Japan.[14]

With this as a background, we expand on this debate and provide some additional perspective: the effect of platinum drugs on the outcome of ovarian cancer is even more relevant today than it was in the past, given the apparent shortcomings of many new drugs that have been tested. The route of platinum administration, as well as patient selection and the role of other drugs, should be central to ongoing research in this area.